Professor Dame Sally Davies, England’s Chief Medical Officer, is right. (Genomics) “has the potential to change medicine forever. . . . The age of precision medicine is now, and the NHS must act fast to keep its place at the forefront of global science.”

It is doubtful whether the UK will be able to maintain its place as a global frontrunner in genomics and personalized medicine. It is even doubtful whether the US, the first nation to discover the genome, and which became preeminent in genomic research, will be able to maintain its position. China, with its well-funded strategy to become the world’s leader in genomics and targeted therapies, is likely to usurp the UK and the US in the next decade.

This Commentary is in 2 parts. Part 1 provides a brief description of the global scientific competition between nation states to turn genomic data into medical benefits. China’s rise, which is described, could have significant implications for the future ownership of medical innovations, data protection, and bio-security. Part 2, which follows in 2 weeks, describes some of the ethical, privacy, human capital and economic challenges associated with transforming genomic data into effective personal therapies.

Turning genomic data into medical benefits

Turning genomic data into medical benefits is very demanding. It requires a committed government willing and able to spend billions, a deep understanding of the relationship between genes and physiological traits, next generation sequencing technologies, artificial intelligence (AI) systems to identify patterns in petabytes (1 petabyte is equivalent to 1m gigabytes) of complex data, world-class bio-informaticians, who are in short supply; comprehensive and sophisticated bio depositories, a living bio bank, a secure data center, digitization synthesis and editing platforms, and petabytes of both genomic, clinical, and personal data. Before describing how the UK, US and China are endeavoring to transform genomic data into personal medicine, let us refresh our understanding of genomics.

Genomics, the Human Genomic Project and epigenetics

It is widely understood that your genes are responsible for passing specific features or diseases from one generation to the next via DNA, and genetics is the study of the way this is done. However, it is less widely known that your genes are influenced by environmental and other factors. Scientists have demonstrated that inherited genes are not static, and lifestyles and environmental factors can precipitate a chemical reaction within your body that could permanently alter the way your genes react. This environmentally triggered gene expression, or epigenetic imprint, can be bad, such as a disease; or good, such as a tolerant predisposition. Epigenetics is still developing as an area of research, but it has demonstrated that preventing and managing disease is as much to do with lifestyles and the environment, as it is to do with inherited genes and drugs. If environmental exposure can trigger a chemical change in your genes that results in the onset of disease, then scientists might be able to pharmacologically manipulate the same mechanisms in order to reverse the disease.

DNA is constantly subject to mutations, which can lead to missing or malformed proteins, and that can lead to disease. You all start your lives with some mutations, which are inherited from your parents, and are called germ-line mutations. However, you can also acquire mutations during your lifetime. Some happen during cell division, when DNA gets duplicated, other mutations are caused when environmental factors including, UV radiation, chemicals, and viruses damage DNA.

You have a complete set of genes in almost every healthy cell in your body. One set of all these genes, (plus the DNA between them), is called a genome. The genome is the collection of 20,000 genes, including 3.2bn letters of DNA, which make up an individual. We all share about 99.8% of the genome. The secrets of your individuality, and also of the diseases you are prone to, lie in the other 0.2%, which is about 3 or 4m letters of DNA. The genome is known as ‘the blueprint’ of life’, and genomics is the study of the whole genome, and how it works. Whole genome sequencing (WGS) is the process of determining the complete DNA sequence of an organism's genome at a point in time.

‘The Human Genome Project’ officially began in 1990 as an international research effort to determine a complete and accurate sequence of the 3bn DNA base pairs, which make up the human genome, and to find all of the estimated 20 to 25,000 human genes. The project was completed in April 2003. This first sequencing of the human genome took 13 years and cost some US$3bn. Today, it takes a couple of days to sequence a genome, and costs range from US$260 for targeted sequencing to some US$4,000 for WGS. Despite the rapidly improving capacity to read, sequence and edit the information contained in the human genome, we still do not understand most of the genome’s functions and how they impact our physiology and health.

Roger Kornberg explains the importance of genomics

Roger Kornberg, Professor of Structural Biology at Stanford University, and 2006 Nobel Laureate for Chemistry, explains the significance of sequencing the human genome, “The determination of the human genome sequence and the associated activity called genomics; and the purposes for which they may be put for medical uses, takes several forms. The knowledge of the sequence enables us to identify every component of the body responsible for all of the processes of life. In particular, to identify any component that is either defective or whose activity we may adjust to address a problem or a condition. So the human genome sequence makes available to us the entire array of potential targets for drug development. . . . . The second way in which the sequence and the associated science of genomics play an important role is in regard to individual variations. Not every human genome sequence is the same. There is a wide variation, which in the first instance is manifest in our different appearances and capabilities. But it goes far deeper because it is also reflected in our different responses to invasion by microorganisms, to the development of cancer and to our susceptibility to disease in general. It will ultimately be possible, by analyzing individual genome sequences to construct a profile of such susceptibilities for every individual, a profile of the response to pharmaceuticals for every individual, and thus to tailor medicines to the needs of individuals.” See video below.

UK’s endeavors to transform genomic data into personal therapies

In 2013 the UK government set up Genomics England, a company charged with sequencing 100,000 whole genomes by 2017. In 2014, the government announced a £78m deal with Illumina, a US sequencing company, to provide Genomics England with next generation whole genome sequencing services. At the same time the Wellcome Trust invested £27m in a state-of-the-art sequencing hub to enable Genomics England to become part of the Wellcome Trust’s Genome Campus in Hinxton, near Cambridge, England. In 2015, the UK government pledged £215m to Genomics England.

DNA testing and cancer“DNA sequencing is simply the process of reading the code that is in any organism . . . It’s essentially a technology that allows us to extract DNA from a cell, or many cells, pass it through a sophisticated machine and read out the sequence for that organism or individual,” says David Bowtell, Professor and Head of the Cancer Genomics and Genetics Program at the Peter MacCallum Cancer Centre, Melbourne, Australia; see video below. “DNA testing has becomeincreasingly widespread because advances in technology have made the opportunity to sequence the DNA of individuals affordable and rapid . . . DNA testing in the context of cancer can be useful to identify a genetic risk of cancer, and to help clinicians make therapeutic decisions for someone who has cancer,” says Bowtell, see video below.

What is DNA sequencing?

What are the advanteges of a person having a DNA test?

Need for National Genome BoardDespite significant investments by the UK government, Professor Davies, England’s Chief Medical Officer, complained in her 2017 Annual Report that genomic testing in the UK is like a “cottage industry” and recommended setting up a new National Genome Board tasked with making whole genome sequencing (WGS) standard practice in the NHS across cancer care, as well as some other areas of medicine, within the next 5 years.

USA’s endeavors to transform genomic data into personal therapies

In early 2015 President Obama announced plans to launch a $215m public-private precision medicine initiative, which involved the health records and DNA of 1m people, to leverage advances in genomics with the intention of accelerating biomedical discoveries in the hope of yielding more personalized medical treatments for patients. A White House spokesperson described this as “a game changer that holds the potential to revolutionize how we approach health in the US and around the world.”

Data management challengesThe American plan did not seek to create a single bio-bank, but instead chose a distributive approach that combines data from over 200 large on-going health studies, which together involves some 2m people. The ability of computer systems or software to exchange and make use of information stored in such diverse medical records, and numerous gene databases presents a significant challenge for the US plan. According to Bowtell, “Data sharing is widespreadin an ethically appropriate way between research institutions and clinical groups. The main obstacles to more effective sharing of information are the very substantial informatics challenges. Often health systems have their own particular ways of coding information, which are not cross compatible between different jurisdictions. Hospitals are limited in their ability to capture information because it takes time and effort. Often information that could be useful to researchers, and ultimately to patients, is lost, just because the data are not being systematically collected.” See video below.

China’s endeavors to transform genomic data into personal therapies

In 2016, the Chinese government launched a US$9bn-15-year endeavor aimed at turning China into a global scientific leader by harnessing computing and AI technologies for interpreting genomic and health data. This positions China to eclipse similar UK and US initiatives.

Virtuous circleTransforming genomic data to medical therapies is more than a numbers race. Chinese scientists are gaining access to ever growing amounts of human genomic data, and developing the machine-learning capabilities required to transform these data into sophisticated diagnostics and therapeutics, which are expected to drive the economy of the future. The more genomic data a nation has the better its potential clinical outcomes. The better a nation’s clinical outcomes the more data a nation can collect. The more data a nation collects the more talent a nation attracts. The more talent a nation attracts the better its clinical outcomes.

TheBeijing Genomics InstituteIn 2010 China became the global leader in DNA sequencing because of one company: the Beijing Genomics Institute (BGI), which was created in 1999 as a non-governmental independent research institute, then affiliated to the Chinese Academy of Sciences, in order to participate in the Human Genome Project as China's representative. In 2010, BGI received US$1.5bn from the China Development Bank, and established branches in the US and Europe. In 2011 BGI employed 4,000 scientists and technicians. While BGI has had a chequered history, today it is one of the world’s most comprehensive and sophisticated bio depositories.

The China National GeneBankIn 2016 BGI-Shenzhen established the China National GeneBank (CNGB) on a 47,500sq.m site. This is the first national gene bank to integrate a large-scale bio-repository and a genomic database, with a goal of enabling breakthroughs in human health research. The gene-bank is supported by BGI’s high-throughput sequencing and bio-informatics capacity, and will not only provide a repository for biological collection, but more importantly, it is expected to develop a novel platform to further understand genomic mechanisms of life. During the first phase of its development the CNGB will have saved more than 10m bio-samples, and have storage capacity for 20 petabytes (20m gigabytes) of data, which are expected to increase to 500 petabytes in the second phase of its development. The CNGB represents the new generation of a genetic resource repository, bioinformatics database, knowledge database and a tool library, “to systematically store, read, understand, write, and apply genetic data,” says Mei Yonghong, its Director.

Whole-genome sequencing for $100The CNGB could also help to bring down the cost of genomic sequencing. It is currently possible to sequence an individual's entire genome for under US$1,000, but the CNGB aims to reduce the price to US$152. Meanwhile, researchers at Complete Genomics, a US company acquired by BGI in 2013, which has developed and commercialized a DNA sequencing platform for human genome sequencing and analysis, are pushing the technology further to enable whole-genome sequencing for US$100 per sample. China's share of the world's sequencing-capacity is estimated to be between 20% and 30%, which is lower than when BGI was in its heyday, but expected to increase fast. “Sequencing capacity is rising rapidly everywhere, but it's rising more rapidly in China than anywhere else,” says Richard Daly, CEO, DNAnexus, a US company, which supplies cloud platforms for large-scale genomics data.

The intersection of genomics and AI Making sense of 1m human genomes is a major challenge, says Professor Jian Wang, former BGI President and co-founder, who has started another company called iCarbonX. Also based in Shenzhen, the company is at the intersection of genomics and AI. iCarbonX has raised more than US$600m, and plans to collect genomic data from more than 1m people, and complement these data with other biological information including changes in levels of proteins and metabolites. This is expected to allow iCarbonX to develop a new digital ecosystem, comprised of billions of connections between huge amounts of individuals’ biological, medical, behavioural and psychological data in order to understand how their genes interact and mutate, how diseases and aging manifest themselves in cells over time, how everyday lifestyle choices affect morbidity, and how these personal susceptibilities play a role in a wide range of treatments.

iCarbonX is expected to gather data from brain imaging, biosensors, and smart toilets, which will allow real-time monitoring of urine and faeces. The Company’s goal is to be able to study the evolution of our genome as we age and design personalized health predictions such as susceptibilities to diseases and tailored treatment options. iCarbonX’s endeavours are expected to dwarf efforts by other US Internet giants at the intersection of genomics and AI.

Ethical challenges

China’s single-minded objective to turn its knowhow and experience of genome sequencing into personal targeted medical therapies has made it a significant global competitive force in life sciences. However, precision medicine’s potential to revolutionize advances in how we treat diseases confers on it moral and ethical obligations. For personal therapies to be effective, it is important that genomic data are complemented with clinical and other personal data. This combination of data is as personal as personal information gets. There could be potential harm to the tested individual and family if genomic information from testing is misused. Reconciling therapy and privacy is important, because privacy issues concerning patients' genomic data can slow or derail the progression of novel personal therapies to prevent and manage intractable diseases. The stakes are high in terms of biosecurity, as genomic research is both therapeutic and a strategic element of national security. While it is crucial to leverage genomic data for future health, economic and biodefense capital, these data will also have to be appropriately managed and protected. Part 2 of this Commentary dives into these challenges a little deeper, and describes some of China’s competitive advantages in the race to become the world’s preeminent nation in genomics and precision medicine.

Takeaways

Despite the endeavours of the UK and US to remain at the forefront of the international competition to transform genomic data into personalized medical therapies for some of the worlds most common and intractable diseases, it seems reasonable to assume that China is on the cusp of becoming the most dominant nation in novel personalized treatments. Notwithstanding, China’s determination to assume the global frontrunner position in genomic science might have blunted its concerns for some of the ethical issues, which surround the life sciences. To the extent that this might be the case the future of humanity might well differ significantly from the generally accepted western vision.

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A number of new studies on ovarian cancer show “promising” results for patients who develop chemo-resistance

A Dutch study uses conventional chemotherapeutics more intensively

Another study uses a new class of drug discovered by the UK’s Institute of Cancer Research

Genetic testing is playing an increasing role in the reduction of chemo-resistance

Since 2014 the Royal Marsden NHS Trust Hospital in London has employed genetic profiling of ovarian cancer patients

The UK’s Chief Medical Officer suggests that whole genome sequencing should become standard practice on the NHS across cancer care

A new class of chemotherapeutic agent is directed at targeting cancers with defective DNA-damage repair

Improvements in cancer care have been both scientific and organizational

Utilizing and sequencing the treatment options for ovarian cancer may have a significant impact on the overall survival rates of patients

Multidisciplinary teams are transforming ovarian cancer care

Improving ovarian cancer treatment

Part II

Part-1 described ovarian cancer, the difficulties of diagnosing the disease early, and the challenges of developing effective screening mechanisms for it in pre-symptomatic women. Here, in part-2, we report new studies, which hold out the prospect of improved treatment options for women living with ovarian cancer. Both Commentaries draw on some of the world’s most eminent ovarian cancer clinicians and scientists.

1

Established chemotherapy agents combined and used intensively

The first study we describe is Dutch, published in 2017 in the British Journal of Cancer. It reports findings of a pioneering type of intensive chemotherapy, which was effective in 80% of patients with advanced ovarian cancer and whose first line of chemotherapy had failed. Currently, such patients have few options because more than 50% do not respond to follow-up chemotherapy.

Intensive combinations

The study, led by Dr. Ronald de Wit, of the Rotterdam Cancer Institute, involved 98 patients who first responded to chemotherapy only later to relapse. Patients in the study were divided into three groups according to the severity of their condition, and treated with a combination of two well established chemotherapy agents: cisplatin and etopside, but the new treatment used the drugs much more intensively than usual.

Usually, chemotherapy is delivered as a course of a number of 21-day sessions (cycles) over several months. Between cycles patients are given time to recover from the toxic side effects, including neurotoxicity, nephrotoxicity, ototoxicity, and chemotherapy-induced nausea and vomiting (CINV). In de Wit’s study the combined chemotherapy drugs were given intensively, on a weekly basis, along with drugs to prevent adverse side effects.

Findings

Among the group of women in de Wit’s study who were most seriously ill, 46% responded to the new treatment, compared with less than 15% for current therapies. The response rates of the two groups of women who were least ill to the new treatment were 92% and 91%. This compares to responses of 50% and 20 to 30% with standard therapies. Overall, 80% of the women's tumours shrank, and 43% showed a complete response, with all signs of their cancers disappearing.

Immediate benefit

"We were delighted by the success of the study. The new drug combination was highly effective at keeping women alive for longer, giving real hope to those who would otherwise have had very little . . . . We were worried the women would be too ill to cope with the treatment, but in fact, they suffered relatively few side effects. And since these drugs are readily available, there's no reason why women shouldn't start to benefit from them right away," says de Wit.

2

ONX-0801 study

The second study we report was presented at the 2017 American Society of Clinical Oncology (ASCO) meeting in Chicago. It describes findings of an experimental new treatment that was found to dramatically shrink advanced ovarian cancer tumors, which researchers suggest is, “much more than anything that has been achieved in the last 10 years”.

“Very promising” findings

Dr. Udai Banerji, the leader of the study, is the Deputy Director of Drug Development at the UK’s Institute of Cancer Research (ICR). Banerji and his team were testing a drug, known as ONX-0801, for safety, but found that tumors, in half of the 15 women studied, shrank during the trial. A response Banerji called, “highly unusual”, and “very promising”. The drug, which is, “a completely new mechanism of action,” could add, “upward of six months to the lives of patients with minimal side effects”. If further clinical studies prove the drug’s effectiveness, it could potentially be used in early-stage ovarian cancer where, “the impact on survival may be better,” says Banerji.

New class of drug

ONX-0801 is the first in a new class of drug discovered by the ICR, and tested with the Royal Marsden NHS Foundation Trust. It attacks ovarian cancer by mimicking folic acid in order to enter the cancer cells. The drug then kills these cells by blocking a molecule called thymidylate synthase. ONX-0801 could be effective in treating the large group of chemo-resistant sufferers for whom there are currently limited options. Additionally, because the new therapy targets cancer cells and does not affect surrounding healthy cells, there are fewer side effects. Further, experts have developed tests to detect the cells that respond positively to this new treatment, which means oncologists can identify those women who are likely to benefit from the therapy the most.

Cautious note

Although the study is said to be “very promising”, Michel Coleman, Professor of Epidemiology at the London School of Hygiene & Tropical Medicine, suggests caution in interpreting its findings as it is such a small study and while, “shrinkage of tumors is important . . . it is not the same as producing the hoped-for extension of survival for women with ovarian cancer.”

3

Genetic testing

Resistance to chemotherapy can be reduced by DNA testing to obtain an increased knowledge of the molecular mechanisms of ovarian cancer pathogenesis, which facilitate personalized therapies that target certain subtypes of the disease. “Some people choose to have DNA testing because either they have developed cancer or family members have,” says David Bowtell, Professor and Head of the Cancer Genomics and Genetics Program at Peter MacCallum Cancer Centre, Melbourne, Australia. “In the context of cancer, personalized medicine is the concept that we look into the cancer cell and understand for that person what specific genetic changes have occurred in their cancer. Based on those specific changes, for that person we then decide on a type of therapy, which is most appropriate for the genetic changes that have occurred in that cancer . . . . . Typically this involves taking a sample of the cancer, running it through DNA sequencing machines, and using bioinformatics to interpret the information. Then, the results, which include gene mutations need to be interpreted by a multidisciplinary team, in order to decide the best possible treatment options for that particular patient,” says Bowtell: see videos below..

How do genetic mutations translate into personalised medicine?

How is personalised medicine implemented?

Mainstreaming cancer geneticsSince 2014 the Royal Marsden NHS Trust Hospital in Londonhas employed genetic profiling of ovarian cancer patients, and have used laboratories with enhanced genetic testing capabilities to streamline and speed up processing time, lower costs, and help meet the large and growing demand for rapid, accurate and affordable genetic testing. The program called, Mainstreaming Cancer Genetics, helps women cancer patients make critical decisions about their treatment options. Currently, fewer than 33% of patients are tested, but this study spearheaded the beginning of a significant change. In her 2017 Annual Report, Professor Dame Sally Davies, England’s Chief Medical Office suggested that within the next 5 years all cancer patients should be routinely offered DNA tests on the NHS to help them select the best personalized treatments.

Bringing genetic testing to patientsAccording to Nazneen Rahman, Professor and Head of the Division of Genetics and Epidemiology at the ICR, and Head of the Cancer Genetics Unit at the Royal Marsden Hospital, London, “There were two main problems with the traditional system for gene testing. Firstly, gene testing was slow and expensive, and secondly the process for accessing gene testing was slow and complex . . . . We used new DNA sequencing technology to make a fast, accurate, affordable cancer gene test, which is now used across the UK. We then simplified test eligibility and brought testing to patients in the cancer clinic, rather than making them have another appointment, often in another hospital.”

More people benefiting from affordable rapid advanced genetic testingTreatment strategies that improve the selectivity of current chemotherapy have the potential to make a dramatic impact on ovarian cancer patient outcomes. The Marsden is now offering genetic tests to three times more cancer patients a year than before the program started. The new pathway is faster, with results arriving within 4 weeks, as opposed to the previous 20-week waiting period. According to Rahman, “Many other centres across the country and internationally are adopting our mainstream gene testing approach. This will help many women with cancer and will prevent cancers in their relatives.” If the UK government acts on the recommendations of Davies, there could be a national center for genetic testing within the next 5 years.

4

PARP Inhibitors and personalized therapy

Since 2 seminal 2005 publications in Nature, (Bryant et al, 2005; and Farmer et al, 2005) which reported the extremely high sensitivity of BRCA mutant cell lines to the enzyme poly (ADP-ribose) polymerase (PARP) inhibition, there has been a scientific race to exploit a new class of cancer drug called PARP inhibitors. The family of PARP inhibitors represents a widely researched and promising alternative for the targeted therapy of ovarian malignancies. Over the past few years, PARP inhibitors have successfully moved into clinical practice, and are now used to help improve progression-free survival in women with recurrent platinum-sensitive ovarian cancer.Recent (PARP) approvalsIn 2014, olaparib was the first PARP inhibitor to obtain EU approval as a treatment for ovarian cancer patients who had become resistant to platinum-based chemotherapy. In 2017, the FDA granted the drug ‘priority review’ as a maintenance therapy in relapsed patients with platinum-sensitive ovarian cancer while confirmatory studies are completed. In December 2016, the FDA granted ‘accelerated approval’ for rucaparib, another (PARP) inhibitor for the treatment of women with advanced ovarian cancers who have been treated with two or more chemotherapies, and whose tumors have specific BRCA gene mutations.

Early in 2017, the drug niraparib was the first PARP inhibitor to be approved by the FDA for the maintenance treatment of adult patients with recurrent gynaecological cancers who are resistant to platinum-based chemotherapy. The approval was based upon data from an international randomized, prospectively designed phase III clinical study, which enrolled 553 patients, and showed a clinically meaningful increase in progression-free survival (PFS) in women with recurrent ovarian cancer, regardless of BRCA mutation or biomarker status. In conjunction with the accelerated 2017 FDA approval for rucaparib, the FDA also approved a BRCA diagnostic test, which identifies patients with advanced ovarian cancer eligible for treatment with rucaparib.

New class of chemotherapiesPARP inhibitors may represent a potentially significant new class of chemotherapeutic agents directed at targeting cancers with defective DNA-damage repair. Currently, these drugs have a palliative indication for a relatively small cohort of patients. In order to widen the prospective patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clearer understanding of the mechanism of action, and a better understanding of their toxicity profile will be required. Once this is achieved PARP inhibitors could to be employed in the curative, rather than the palliative setting.

5

The future of cancer care and multidisciplinary teams

According to Hani Gabra, Professor of Medical Oncology at Imperial College, London; and Head of AstraZeneca’s Oncology Discovery Unit, we now have “many options” for treating ovarian cancer. However, “how we utilize and sequence these options may have a significant impact on the overall survival of a patient. Better understanding of the disease through science is constantly turning up new options. For the first time in the last 5 years we are developing options in real time for patients. Patients almost are able to benefit from these options as they are relapsing from their disease. Keeping patients alive for longer allows them to access new treatments . . . It’s truly remarkable to see this in real time as a doctor,” says Gabra: see video.

A significant number of mostly private patients diagnosed with ovarian cancer draw comfort from the belief that they, “have the best oncologist”. This view fails to grasp the challenges facing individual clinicians acting on their own to treat a devilishly complex disease such as ovarian cancer. “The main improvements in cancer care have been organizational and scientific.” says Gabra. “It is not enough to create new science and new treatments. It is also important to rigorously implement these. The most effective way to do this is via a ‘tumor board’ or a ‘multidisciplinary clinic or team’, where various specialists such as surgeons, radiotherapists, medical oncologists, pathologists, clinical nurse specialists, etc come together and discuss each individual patient. Such multidisciplinary discussion results in the best utilizations of currently available treatment options in the right sequence. It’s difficult to do this for a doctor acting on his or her own and making isolated decisions . . . Multidisciplinary decision-making has transformed cancer care,” says Gabra: see video.

Takeaways

This Commentary provides a flavor of some of the recent advances in ovarian cancer research and care, and suggests that treatment options have improved in the 4 years since Maurice Saatchi described ovarian cancer care as, “degrading, medieval and ineffective” leading “only to death”. However, it is worth stressing that care is both organizational and scientific, and multidisciplinary teams can transform care and prolong life.